Bipolar disorder is a prevalent and severe psychiatric disorder marked by alternating episodes of depression and mania. In the Department of Veterans Affairs (VA), nearly 80,000 Veterans received care for bipolar disorder in 2004, a 40% increase from 1999. Bipolar disorder imposes a substantial medical burden on Veterans, and is associated with the highest health care costs of any psychiatric disorder in the VA system. Moreover, in male Veterans bipolar disorder is a significant risk factor for suicide. The World Health Organization ranks bipolar disorder as the sixth leading cause of global medical disability. Despite decades of research, the illness remains poorly understood, and no new treatment has surpassed lithium's effectiveness for the majority of patients. There is a critical need for research studies aimed at understanding the neurobiology of bipolar disorder, to improve our diagnostic and treatment strategies. Brain pH is closely linked to affective functioning, and is influenced by a range of internal and external factors. One such environmental factor may be altitude. Extreme altitudes are associated with a decreased partial pressure of inspired oxygen, and this hypobaric hypoxia results in significant cognitive impairment. However, the effect of moderate changes in altitude on brain chemistry is not well understood. Recent publications show that within the U.S., altitude is associated with an increased rate of suicide that begins at the modest altitude of ~2,000 feet, an effect that may be strongest in bipolar disorder. In terms of endogenous factors, it is hypothesized that decreased brain pH in bipolar disorder may represent a biologic trait of the illness. Decreased brain pH has been linked to altered brain lactate and glutamate levels in bipolar disorder. Research is needed to clarify the relationship between mood, brain chemistry and altitude in bipolar disorder. To address this need, we propose to use magnetic resonance spectroscopy (MRS) neuroimaging together with clinical assessments, to study the relationship between brain pH, glutamate, lactate and altitude in Veterans with bipolar disorder. The proposal features a novel cross-sectional study design, in which brain scans will be performed on subjects with bipolar disorder at two altitudes: Salt Lake City, UT (4,700 feet) and Belmont, MA (44 feet). A total of 120 subjects will be enrolled, including 40 depressed bipolar subjects (20 per site), 40 euthymic bipolar subjects (20 per site), and 40 healthy controls (20 per site). All subjects will undergo MRS brain scans to measure their brain pH, glutamate and lactate levels. The proposed study will provide insight into the interrelationship of brain chemistry, mood state and altitude in bipoar disorder. The results of the study may help scientists develop new diagnostic methods, or new treatment approaches for Veterans with bipolar disorder.